Bile acids are amphiphilic molecules synthesized from cholesterol in the liver. They are physiological detergents that maintain cholesterol homeostasis (Staels B, Fonseca V. A., Bile acids and metabolic regulation: mechanisms and clinical responses to bile acid sequestration, Diabetes Care. 2009 November; 32 Suppl 2:S237-45.). Bile acid synthesis is a multi-step process consisting of two distinct pathways, the classical and the alternate. The classical pathway accounts for the majority of bile acids produced. Hydrophobic cholic acid (CA) is the major resulting bile acid and cytochrome P450, family 8, subfamily B, polypeptide 1 (Cyp8b1) plays a critical role in its production. Inhibition of Cyp8b1 reduces the amount of cholic acid in the overall bile acid pool which causes an increase in the amount of alternative bile acids to make up for the deficiency. In humans, the other major bile acid is chenodeoxycholic acid (CDCA) and the amount of CDCA is increased upon inhibition of Cyp8b1. This has been demonstrated in a mouse model.
Mice with targeted disruption of Cyp8b1 (Cyp8b1−/−) fail to produce CA. (Li-Hawkins J, Gafvels M, Olin M, Lund E G, Andersson U, Schuster G, et al, Cholic acid mediates negative feedback regulation of bile acid synthesis in mice. J. Clin. Invest. 377 20020 ct.; 110(8): 1191-200). The fraction of the bile acid pool that would have been occupied by CA is predominantly replaced by hydrophilic bile acid species, α- and β-muricholates, in Cyp8b1−/− mice (since CDCA is converted into muricholic acid (MCA) in rodent livers, the main bile acids found in rodents are CA/MCA instead of CA/CDCA in humans). The resulting increase in hydrophilic bile acid species leads to a reduction in both intestinal absorption and hepatic accumulation of cholesterol (Murphy C, Parini P, Wang J, Björkhem I, Eggertsen G, Gifvels M, Cholic acid as key regulator of cholesterol synthesis, intestinal absorption and hepatic storage in mice, Biochim. Biophys. Acta. 2005 Aug. 15; 1735(3): 167-75). Cyp8b1−/−×ApoE−/− mice show reduced atherosclerotic plaques, owing to decreased levels of apolipoprotein B (ApoB)-containing lipoproteins in the plasma, reduced hepatic cholesteryl esters and enhanced bile acid synthesis (Slatis K, Gafvels M, Kannisto K, Ovchinnikova O, Paulsson-Berne G, Parini P, et al., Abolished synthesis of cholic acid reduces atherosclerotic development in apolipoprotein E knockout mice, J. Lipid Res. 2010 November; 51(11):3289-98). Furthermore, cholesterol fed Alloxan induced type 1 diabetic Cyp8b1−/− mice are protected against hypercholesterolemia and gall stones (Wang J, Gafvels M, Rudling M, Murphy C, Bjorkhem I, Einarsson C, et al., Critical role of cholic acid for development of hypercholesterolemia and gallstones in diabetic mice, Biochem. Biophys. Res. Commun. 2006 Apr. 21; 342(4):1382-8). These findings suggest that the absence of Cyp8b1 may be beneficial in cases of metabolic syndrome.
Also, it has been found that absence of Cyp8b1 results in improved glucose tolerance, insulin sensitivity and 3-cell function, mediated by absence of CA in Cyp8b1−/− mice (Achint Kaurl, Jay V. Patankar, Willeke de Haanl, Piers Ruddlel, Nadeeja Wijesekaral, Albert K. Groen, C. Bruce Verchere, Roshni R. Singaraja and Michael R. Hayden, Loss of Cyp8b1 improves glucose homeostasis by increasing GLP-1, Diabetes, Published online before print Oct. 22, 2014, doi: 10.2337/db14-0716). The absence of biliary CA results in reduced intestinal fat absorption and leads to increased free fatty acids reaching the ileal L-cells. Increased free fatty acids reaching the ileal L-cells, causes the ileal L-cells to increase secretion of the incretin hormone glucagon like peptide-1 (GLP-1). GLP-1 in turn increases the biosynthesis and secretion of insulin from β-cells, leading to the improved glucose tolerance observed in the Cyp8b1−/− mice.
Thus, inhibition of Cyp8b1 causes a decrease in cholic acid (CA) levels and an increase in chenodeoxycholic acid (CDCA) levels. Altering the CA/CDCA ratio plays an important role in cholesterol absorption and homeostasis. As such, there is a need for Cyp8b1 inhibitors that are useful in treating cardiometabolic diseases associated with elevated LDL, such as atherosclerosis, fatty liver and nonalcoholic steatohepatitis (NASH). Also, there is a need for Cyp8b1 inhibitors that are useful for treating noninsulin-dependent diabetes (NIDDM), hyperglycemia, and other symptoms associated with NIDDM.